Substituted carboximidic acid esters of 7-(2-mercaptoacetamido) cephalosporanic acid derivatives

ABSTRACT

Substituted carboximidic acid esters of 7-(2-mercaptoacetamido) cephalosporanic derivatives which are prepared by the reaction of the appropriately substituted thioamide with an appropriate 7-(2haloacetamido) cephalosporanic acid derivative. The compounds are antibacterial agents.

[451 Dec. 2, 1975 [54] SUBSTITUTED CARBOXIMIDIC ACID $646,025 2/1972 Crust, Jr 260/243 c ESTERS 0 7 (Z MERCAPTOACETAMIDO) 3,839,329 1/1974 Breuer et al 260/243 C CEPHALOSPORANIC ACID DERIVATIVES [75] Inventor: Peter H. L. Wei, Springfield, Pa. Primary Examiner-Donald G. Daus A. .t E. -D G. R m1 Corporation, New York, NY. g

[22] Filed: Mar. 18, 1974 [21] Appl. No.1 452,014 [57] ABSTRACT Substituted carboximidic acid esters of 7-( 2- [52] [1.5. Cl;Z 260/243 C; 424/246 mercaptoacetamido) cephalosporanic derivatives {5 Int- CL are prepared the reaction of the appropri- A61K 31/545 ately substituted thioamide with an appropriate 7-(2- [58] P191611 01 Search 260/243 C hal a ta id ephalosporanic acid derivative, The

compounds are antibacterial agents. [56] References Cited UNITED STATES PATENTS 23 Claims, N0 Drawings 3,627,760 12/1971 Bickel at a]. 260/243 C 1. SUBSTITUTED CARBOXIMIDIC ACID ESTERS OF 7-( Z-MERC APTOAC ETAMIDO) CEPHALOSPORANIC ACID DERIVATIVES DESCRIPTION OF THE INVENTION In accordance with this invention there is provided antibacterial agents of the formula:

A'is a member selected from the group consisting of alkyl of l to 6 carbon atoms;

in which R is alkyl of 1 to 6 carbon atoms;

arylcarboxamidomethyl of 8 to 12 carbon atoms; alkanoylamidornethyl of 3 to 8 carbon atoms;

a-cyanobenzyl;

in which R is hydrogen, dialkylamino of 2 to carbon 35 atoms or halo and p is O or 1;

/s NHCO(CH s a 2 n C BCH2 TNQK v i ll 1 B is a member selected from the group consisting of H, alkanoyloxy of 2 to 6 carbon atoms,

or, when taken with the 3-carboxy group,

M is a member selected from the group consisting of -H, an alkali metal and -NH R is a member selected from the group consisting of H, alkyl of l to 6 carbon atoms and aryl of 6 to 10 carbon atoms; R is a member selected from the group consisting of H, alkyl of 1 to 6 carbon atoms and aryl of 6 to 8 carbon atoms; 11 is one of the integers 0, l or 2; and the pharmaceutically acceptable acid addition salts thereof. The compounds of this invention are prepared by reaction of an appropriately substituted thioamide with an appropriate 7form, 2-haloacetamido)cephalosporanic acid derivative. The reactants are dissolved in acetone and stirred at a temperature generally between 10 and 25C. for a period of from about 4 hours to 24 hours. Any solid material is removed from the reaction solution by filtration and the solvent is removed under reduced pressure at a temperature below 30C. The product is then triturated with diethyl ether and the product is recovered as a polymorphous material. For ease in processing, the products are generally recovered in the hydrohalide addition salt form frequently with small amounts of solvent, the latter being readily removed by further vacuum stripping of the product. The free bases are readily formed by neutralization of the hydrohalide by conventional techniques.

As used throughout this specification, the term alkyl" is intended to embrace univalent aliphatic hydrocarbon radicals such as methyl, ethyl, propyl, i-propyl, butyl, i-butyl, amyl and hexyl. The expression arylcarboxamidomethyl of 8 to 12 carbon atoms; is intended to embrace such radicals as benzoylamidomethyl groups in which from 1 to 5 alkyl groups may be present containing a total of 4 carbon atoms. The expression alkanoylamidomethyl of 3 to 8 carbon atoms: is intended to embrace those unbranched lower fatty acid amidomethyl groups in which the fatty acid contains from 2 to 7 carbon atoms. The term halo is intended to embrace chlorine, bromine, iodine or fluorine, preferably chlorine or bromine. The alkali metals intended to be embraced are sodium and potassium. The term aryl is intended to embrace those monovalent aromatic hydrocarbons whose single valence bond belongs to the nucleus such as phenyl, naphthyl,.tolyl, ethylphenyl and dimethylphenyl, as limited by the recited number of carbon atoms. g

The preferred compounds of this invention are those derived from readily available reactants which are most economical to produce and efficacious in use. presenting the formula:

--c s -c H CONH iia 11 CHZB wherein A is a member selected from the group consisting of alkyl of l to 6 carbon atoms;

in which R is alkyl of 1 to 6 carbon atoms;

benzamidomethyl; acetamidomethyl; a-cyanobenzyl;

aryl of 6 to 8 carbon atoms 1 dimethylaminophenyl; phenylthio;

; and

and the pharmaceutically acceptable acid addition I salts thereof. The compounds of this invention are active antibacterial agents, effective against gram-positive and gramnegative bacteria as well as penicillin resistant staphlococcus. The activity of the compounds was established by treating various bacteria colonies grown under controlled conditions with various concentrations of aqueous solution of the compounds of this invention in accordance with the well known, scientifically accepted agar serial dilution testing technique, to determine the minimum inhibitory concentration (MIC) ofeach compound. Hence, the compounds of this invention, being effective in the control of bacterial infestations. are useful in the fields of comparative pharmacology and microbiology and for the control and comparative analysis of bacterial colonies. The compounds are to be used to inhibit the growth of bacteria in the conventional manner and by the known methods of utilizing cephalosporin derivatives.

The following examples illustrate the preparation of representative cephalosporin derivatives of this invention. The activity of each exemplified product is presented for those specific bacterial strains against which the compound exemplified was active at or below 250 micrograms per milliliter. The representative nature of the bacterial strains employed to demonstrate anti-bacterial activity are indicative of the broader applicability of the compounds disclosed herein in the control of bacterial infestations other than those specifically referred to in each of the following examples. The bacteria are named, followed by the specific strain and the concentration at which percent inhibition occurred. The abbreviations for each bacterium are:

BA SU Bacillus subtilis BO BR Bordetclla brochiseptica EN AE Entcrobactcr acrogenes ST AU Staphylococcus aureus ES CO Escherichia coli ES 1N Escherichia intcrmcdia HE SP Hercllca species NE CA Neisseria catarrhulis SA PA Salmonella paratyphi Kl. PN Klebsiclla pneumoniae PR VU Proteus vulgaris EXAMPLE 1 7-12-(p-Dimethylamino-N-methylbenzimidoylthio)acetamido]cephalosporanic acid.

7-(Z-Bromoacetamido)cephalosporanic acid (0.39 gram. 1 millimole) and p-dimethylamino-N-methylthiobenzamide (0.19 gram, 1 millimole) are dissolved in acetone. The solution is stirred at room temperature for four hours and stored in a refrigerator overnight. The solvent is removed and the residual solid (0.5 gram) is triturated with diethyl ether to yield the title compound as the hydrobromide salt.

Elemental Analysis for C H N O S HBL1/2(C H O:

Calc'd: C, 46.15; H. 5.17; N. 8.97. Found: C. 46.68; H. 5.44; N, 9.27.

7- 2-( p-Chlorobenzimido ylthio )acetamido]cephalosporanic acid.

The procedure of Example 1 is repeated with the exception that p-chloro-thiobenzamide is reacted with ranic acid is reacted with N-(l-naphthyl)thioaceta-.

mide. The title compound is isolated asits hydrobromide salt.

il Analysis fOII 111 111 n 6 g- L l 5)3 Elemental Analysis for C;,1.H 1;N3O,;S- ,.HB1'.2IIZHQO:

Calc'd: C. 4l.9l1 H. 41021N. 6.98. Calcd: C. 50.35: H. 4.65. N. 5.87. F9und= H N9 FOunLlI C. 50.29; H. 4.24; N. 6.20. BA SU 6633 .488 BA 51; 33 43 B0 BR 4617 250 ST AU 6538P .976 ES Co 9637 250 10 st AL SMITH .976 HE SP 9955 250 ST AU CHP 3911 K1. PN 10031 625 ST AL 53 1110 1.95 NE CA 8193 125 NE CA 8193 625 PR vu 6896 250 ES CO 9637 62.5 5A PA 11737 135 SA PA 11737 125 ST AU 6538P 3.90 BO BR 7 3 ST AU SMlTH 3.90 PR VL 6896 15 ST AU CHP HE SP 9955 250 sT AU 53 1so 15.6

EXAMPLE 6 EXAMPLE 3 7-(Z-Mercaptoacetamido)cephalosporanic acid ester 7[2-(acetamidoylthio)acetamido]cephalosporanic with N-phenylthioacetamidic acid.

The procedure of Example 3 is repeated with the ex The procedure of Example 1 is repeated with the exception'that N-phenylthioacetamide is reacted with 7- ception that thioacetamide is reacted with 7-(2- C2-bromoacetamido)-cephalosporanic acid. The prodb omoace ido)-Cephalosporanic acid. The title uct is then isolated as the hydrobromide acid addition compound is recovered as the hydrobromide addition salt. salt.

Elemental Analysis for C2,H. ,N 1O"S1 ..HBL l/3(CH ,CO: E] m A ClllCLlI C. 44.57; H. 4.63; 7.15. 233E93 3531 1233 3O FOUflLlZ C. 44.91. H. 4.91; N. 6.77.

Found: C. 33.58; H. 4.34; N. 8.57. BA P BA SU 33 488 ST AL 6538p .976 B0 BR 46 63 ST AL SMITH .976 HE SP 9955 250 5T AU 1 5T AU 53-11 0 1.95 R1. PM 10031 -50 7 PR vu 6896 250 35 NE (A sA PA 11737 125 E5 CO 9637 ST AU 976 SA PA 11737 15.6 ST AU SMITH KL PN 10031 31.3 $7" AU CHP 62.5 80 BR 4617 ST. AU 53-]80 125 v EXAMPLE 7 EXAMPLE 4 7-(2-Mercaptoacetamido)cephalosporanic acid ester 7-(2-Mercaptoacetamido)cephalosporanic acid ester with thioisonicotinimidic, acid.

wlth N-( l-naphthyl)thl0a acld- The procedure ofi Example I is repeated with the ex The procedure of Example 3 is repeated with th ception that thioisonicotinamide is reacted with 7-(2- ception that N-( l-naphthyl)thioacetamide is reacted bfOmOflCetfimlClO)CePhZIlOSPOFBJIiC d T e 'c COmi h 7-(Z-bromgacetamido)cephalosporanic id Th pound 1s recovered as the hydrobromide addmon salt. product is isolated as the hydrobromide addition salt.

Elemental Analysis for C l-l N o S hHBr.l/5(C H O: Elemc l l analysis fort C,,1H,,.N,O.;S2.HB1.(C2H5)2O Calcd: C, 48.88; H. 4.30; N. 6.90. @1611; C. 43.63: H 4.83; N. 9.25. Found: C. 49.00; H. 4.95; N. 6.35. Found: C. 43.981H. 5.93; N. 9.13. BA SU 6633 .244 BA SU 6633 .488 ST AU 6538P .488 ST AU 6538P .976 ST AU SMITH .488 ST AU SMITH .976 ST AU CHP 195 ST AU CHP 3.90 ST AU 53-1110 1.95 ST AU 53 I80 3.90 NE CA 8193 62.5 NE CA 8193 125 ES (:0 9637 625 S CO 9637 125 5A PA 11737 15.6 sA PA 11737 31.3 KL PN 10031 250 KL PN W031 313 B0 BR 4617 62.5 BO BR 4617 125 PR V11 6896 62.5 PR U 68 6 62.5 HE SP 9955 2 HE SP 9955 125 EXAMPLE 5 EXAMPLE 8 7-( 2-Mercapto-2-phenylacetamido )cephalosporanic acid ester with N-( l-naphthyl)thioacetamidic acid.

The procedure of Example 4 is repeated with the exception that 7-(2-bromophenylacetamido)cephalospo- 7-( 2-Mercapto-2-phenylacetamido )cep halosporanic acid ester with thioisonicotinimidic acid.

The procedure of Example 7 is repeated with the exception that 7-(2-bromo-2-phenylacetamido)cephalosporanic acid is employed as the reactant instead of 7- (Z-bromoacetamido) cephalosporanic acid. The title compound is recovered as the hydrobromide addition salt.

Elemental Analysis for C ,H. N O.;S. .HBr.1/2H. ,O

Calc'd: C. 46.76: H. 3.92: N. 9.09. Found: C. 46.84: H. 4.18: N. 8.46.

BA 51; 6633 .488 51 AL 6538P .976

ST AL' SMITH .976 ST AL CHP 3.911 57 AL s3 1so 3.90 NE CA 8193 31.3 ES C 9637 125 A PA 11737 31.3

KL P.\' 111031 15.6

130 BR 4617 123 PR \1: 6896 12s EXAMPLE 9 7-[(Z-Mercaptoacetamido)-3-methyl-8-oxo-5-thia-1- azabicyclo-4.2.0]oct-2-ene-2-carboxylic acid ester with thicnicotinimidic acid.

The procedure of Example 7 is repeated with the exceptions that thionicotinamide is reacted with 7-(2- bromoacetamido )-3-methyl-8-oxo-5-thial -azabicyclo[4.2.0loct-2-ene-2-carboxylic acid. The product is recovered as the hydrobromide addition salt.

Found: C. 43.67: H. 415011. 1048.

BA SL' 6633 7.81

ST AL' 6538P 15.6

ST AL SMITH 156 ST AL CHP 625 ST AL 53-180 62.5

EXAMPLE 1O 7-(2-Mercaptoacetamido)cephalosporanic acid ester with thio-Z-thiophenecarboximidic acid.

7-( Z-Bromoacetamido)cephalosporanic acid is dissolved in acetone with an equimolar amount of 2-(2- thieny1)thioacetamide. The solution is stirred for approximately four hours, cooled and the solvent is evaporated. The residual material is triturated with diethyl ether to yield the title compound as the hydrobromide acid addition salt.

Elemental Analysis for CHHHNQOGSfl-HBT1/2(CH3)2CO-1/2(C2H3)20 Calc'd: C. 40.86: H. 4.35: N. 6.97. Found: C. 40.64: H. 4.34: N. 7.16.

BA SU 6633 .031 ST AU 6538P .976 ST AL SMITH .061 ST AU CHP 15.6 ST AU 53-180 7.81 NE CA 8193 250 ES CO 9637 250 ES 1N 65-1 250 SA PA 1 1737 125 EN AE 13048 250 KL PN 10031 125 B0 BR 4617 250 PR VU 6898- 250 HE SP 9955 125 EXAMPLE 1 1 7-( Z-Mercaptoacetamido )-3-methyl-8-oxo-5-thial azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid ester with thio-2-thiophenecarboximidic acid.

The procedure of Example 10 is repeated with the exception that 7-(Z-bromoacetamido)-3-methyl-8-oxo- S-thia-l-azabicyclo[4.2.()]oct-2-ene-2-carboxylic acid is employed rather than 7-(2-bromoacetamido)cephalosporanic acid. The product is isolated as the hydrobromide addition salt.

Calc'd: C. 39. 6; H. 4.12: N. 7.99.

Found: C. 39.37. H. 4.19; N. 7.22.

BA SU 6633 31.3

ST AL' 6538P 15.6

ST AL' SMITH 15.6

ST AL' CHP 62.5

ST AU 53-180 62.5

EXAMPLE l2 7-( Z-Mercapto-Z-phenylacetamido )cephalosporanic acid ester with thio-Z-furancarboximidic acid.

7-(2-Bromo-2-phenylacetamido)cephalosporanic acid is dissolved in acetone with an equimolar amount of Z-thiofuramide. The solution is stirred for approximately four hours at room temperature, cooled and the solvent is evaporated. The residual material is triturated with diethyl ether to yield the title compound as the hydrobromide and addition salt.

Elemental Analysis for C23H2 N3O7SpHBf-1/3(CH3)2C0-1/2H2O Calcd: C. 46.1921'1. 4.121N. 6.74. Found: C. 46.64; H. 4.26; N 6.49.

BA SU 6633 .488 ST AU 653 SF 1.95 ST AU SMITH 1.95 ST AU CHP 1.95 ST AU 53-180 1.95 NE CA 8193 62.5 ES CO 9637 62.5 SA PA 11737 62.5 KL PN 10031 15.6 BO BR 4617 PR VU 6898 62.5

EXAMPLE l3 7-(2-Mercaptoacetamido )cephalosporanic acid ester with 3-iminothiobutyrimidic acid.

The procedure of Example 1 is repeated with the exception that 3-iminothiobutyramide is substituted for p-dimethylamino-N-methylthiobenzamide as the reactant, and acetone is employed as the reaction solvent medium. The product is isolated as the hydrobromide addition salt.

Elemental Analysis for C H ,N..O,.S .HBr.1/5(C H O.1/2H O Calc'd: C. 37.84: H. 4.54: N. 10.55. Found: C. 37.86; H. 4.47; N. 992.

BA so 6633 .244 ST Au 6538? .976 ST AU SMITH .976 ST AU CHP 3.90 ST AU 53 v NE CA 8193 62.5 ES C0 9637 31.3 SA PA 11737 15.6 KL PN 10031 '15.6

-continued -continued PR VU 6896 125 B BR 4617 15.6 HE SP 9955 125 PR vU 6896 7.31

HE SP 9955 125 EXAMPLE 14 EXAMPLE 17 7-( 2-Mercapto-2-phenylacetamido )cephalosporanic z'MerFaptoacetamldo q P9 acid ester acid ester with 3-iminothiobutyrimidic acid. 1 0 lbenzmmdothloacetlmldw The procedure of Example 13 is repeated with the substamlally equlmolar cluumltles 0f 7 exception that 7-(2-bromo-2-phenylacetamido)cephbmrlloacefmmldol9ephalosliommc .acld and benalosporanic acid is employed asthe initial reactant zamldothloacetamlde are dissolved in acetone and reacted at a temperature between 10 to C. Some in- 5 soluble material is removed by filtration, the solvent Elemcntlll Analysis for .C22H24N4O6S2HBL 1 /2(C2H -,)2O. 1/411. ,o

CulCdI c. 45.96: H. 4.90. N. 8.93. Found: C. 46.30; H. 5.28; N. 8.88.

BA SU 6633 .976 ST AU 6538P 3.90 ST AU SMITH 3.90 sT AU CHP 15.6 ST AU 53 1s0 7.31 NE CA 8193 250 ES CO 65-1 125 KL PN 10031 125 B0 BR 4617 250 PR VU 6896 250 EXAMPLE l5 Elemental Analysis for C H N O S .HBr.(CH CO.2H O

Calcd: C. 42.49; H, 4.57. N. 9.91. Found: C. 42.41; H, 4.11; N. 9.46.

BA SU 6633 7.31

ST AU 65381 15.6

ST AU SMITH 15.6

ST AU CHP 62.5

ST AU 53-180 62.5

EXAMPLE 16 7-( 2-Mercapto-Z-phenylacetamido )cephalosporanic acid ester with 2-acetamido-thioacetimidic acid.

The procedure of Example 12 is repeated with the exception that 2-acetamidothioacetamide is used rather than 2-thiofuramide.

Elemental Analysis for BA SU 6633 122 ST AU 6538P .244 ST AU SMITH .2 14 ST AU CHP .976 ST AU 53-180 .488 NE CA 8193 15.6 ES CO 9637 7.81 ES 1N 651 250 SA PA 11737 3.90 KL PN 10031 7.81

evaporated in vacuo at a temperature below C. and the residue is triturated with diethyl ether and recovered as the title compound in its hydrobromide addition salt form.

Elemental Analysis for C ,H N.O S .HB1'.H. ,O:

Calcd: C. 41.651H. 4.16: N. 9.25. Found: C. 41.67: H. 4.45: N. 9.39.

BA SU 6633 .122 ST AU 6531 P .976 25 ST AU SMITH .976

ST AU CHP 3.90 ST AU 53 180 1.95 NE CA 8193 62.5 ES C0 9637 250 5. PA 11737 62.5 KL PN 10031 125 30 PR VU 6396 125 EXAMPLE 18 7-(2-Mercaptoacetamido )cephalosporanic acid ester with N-phenylthiobenzimidic acid.

The procedure of Example 6 is repeated with the exception that N-phenylthiobenzamide is employed rather than N-phenylthioacetamide to obtain the title compound as the hydrobromide addition salt.

7-(Z-Mercaptoacetamido)cephalosporanic acid ester with Z-cyano-Z-phenylthioacetimidic acid.

The procedure of Example 17 is repeated with the exception that 2-cyano-2-phenylthioacetamide is used as the reactant in lieu of 2-benzamidothioacetamide. The product is recovered as the hydrobromide addition salt.

Elemental Analysis for C ,H .,N.,O S.HBr.3H. .O.l/4(CH,,) CO.l/6(C H5)2O Calc'd: C, 41.43: H. 4.68: N. 8.62. Found: C. 40.891H. 3.99: N. 8.36. BA SU 6633 ST AU 6538P -continued -continued sT AU SMITH .488 ES C 9637 7x1 ST AL: CHP 1.95 Kl. PN 111031 250 r AL- 53 11 (1 .976 NE CA 8193 7.81 NE CA 8193 31.5 PR \'L' 6896 125 ES C0 9637 150 ST AL 6538P .976 sA PA 11737 7.81 ST AL SMITH .4xx BO BR 46l7 1 313 5r AL CHP 195 PR \'L 6896 15.6 s'r AL 53 1811 3.90 HE SP 9955 o l0 1 What is claimed is: EXAMPLE 2O 1. compound Of the formula: 7-( Z-Mercaptoacetamido )cephalosporanic acid ester 5 with phenyld1th1o1m1docarbon1c acld 7-phenyl'ester. 15 .WCHMCONH 7-(2-Bromoacetamido)cephalosporanic acid (0.79 H A N 2 8 gram, Z-millimole) and N,S-diphenyl d1th1ocarbamate (Crosby and Niemann, J1A.C.S. 76, 4458-4463( 1954) O (0.49 gram, 2 millimole) and sodium bicarbonate (0.25 c M gram, 3 millimole) are dissolved in aqueous acetone 2 and heated in'a water bath (60C.) for 6 hours. After removing some insoluble material by filtration, the solwherein Vent is f q' W addefl to the resldue and A is a member selected from the group consisting of the resulting solution is acidified with 6N HCl Th e prealkyl of 1 to 6 Carbon atoms; cipitated solid is washed with water. dissolved in ace- 5 tone, filtered and again evaporated. The solid (0.35 Rita-Ch gram) is triturated with diethyl ether and recovered. 2

7-( Z-Mercapto-Z-phen ylacetamido )cephalosporanic acid diester with dithiooxalimidic ester.

CHCONH SC=NH An acetone solution of dithiooxamide (0.12 gram, 1 millimole) and 7-(2-bromo-2-pheriylacetamido)cephalosporanic acid (0.46 gram, 1 millimole) is stirred in an ice bath for 2 hours. Some insoluble material is re-.

moved by filtration and the acetone is evaporated. The residue is triturated with diethyl ether and the polymorphous product (0.45 gram) is recovered.

Elemental Analysis for (C ,H N -,O,;S .HBr) .l/2(C H,,) O Calcd: C. 43.82: H. 3.95; N. 7.67. Found: C. 44.58; H. 3.92; N, 7.30.

BA SU BO BR 30 in which R is alkyl of l to 6 carbonatoms;

arylcarboxamidomethyl of 8 to 12 carbon atoms; alkanoylamidomethyl of 3 to 8 carbon atoms; a-cyanobenzyl;

R4 I Q- s 40 in which R is hydrogen, dialkylamino of 2 to 6 carbon atoms or halo and p is O or 1;

, W;- cn o ccna in which Xis O, S or NH;

13 14 where R is hydrogen, alkyl of l to 6 carbon atoms and B is a member selected firom the group consisting of phenyl; and i l-l and acetoxy;

M is a member selected from the group consisting of S H, an .alkali metal and NH NHCO(CHQ)"CIHS fi 1 .R is a member selected from the group consisting of BCH. N R2 H. alkyl of-l to 6 carbon atoms, phenyl, tolyl,

O ethylphenyl, dimethylphenyl and naphthyl; co M R is a member selected from the group consisting of 2 H, alkyl of l to 6 carbon atoms, phenyl, tolyl, di-

methylphenyl and ethylphenyl; and the pharmaceutically acceptable acid addition salts B is a member selected from the group consisting of th f alkfmoyloxy of 2 to 6 Carbon atomsor when 3. The compound of claim 1 which is 7-[2-(p-dimetaken with the group, thylamino-N-methylbenzimidoylthio)acetamidolcephalosporanic acid. H 4. The compound of claim 1 which is 7-[2-(pchlorobenzimidoylthio)acetamido]cephalosporanic acid.

5. The compound of claim 1 which is 7-[2-(acetimid- M is a member selected from the group consisting of oylthio) acetamidokephalospomnic acid.

an alkah metal and NH"; 6. The compound of claim 1 which is 7-[2-mercap- R 15 a member Selected from the group Conslstmg of toacetamido) cephalosporanic acid ester with thi- H, alkyl of l to 6 carbon atoms and aryl of 6 to Oisonicotinimidic acid 10 carbon atoms 2 7. The compound ofclalm 1 which Is 7-(2-mercapto- R gi rg; z g g rgg gii sgg gffg g g Z-phenylacetamido)cephalosporanic acid ester with 8 carbonyatoms y thioisonlcotmimldic acid. l

n is one of the integers O l or 7' and 8. The compound of claim 1 which is 7-(2 -mercaph h in 1 bl ddt. l toacetamido) cephalosporanic acid ester with N-(lthzrepfiarmaceu ica y accep a c act a llOIl sa t hthyl)thi0acetimidic acid.

2 A compound of claim 1 of the formula" The compound of Glam 1 wluch 1s 7'(.2 mer.wp

' toacetamido) cephalosporanic acld ester with th1o2- thiophenecarboximidic acid.

s 10. The compound of claim 1 which is 7- (2-mercapll toacetamidoJ-3-methyl-8-oxo-5-thra-l-azabicy- N CH 2 B clo[4.2.0]oct-2-ene-2-carboxylic acid ester with thio 2-thiophenecarboximidic acid.

l 11. The compound of claim 1 which is 7-(2-mercapco M toacetamido)-3-methyl-8-oxo-5-thia-1-azabicy- 2 40 clo[4.2.0]oct-2-ene-2-carboxylic acid ester with thionicotinimidic acid.

12. The compound of claim 1 which is 7-(2-mercapto-Z-phenylacetamido)cephalosporanic acid ester with N-( l-naphthyl)thioacetimidic acid.

13. The compound of claim 1 which is 7-(2-mercap- R-CC 2. toacetamido) acid ester acid with 5-oxo-3-phenyl-2- pyrazolinel -carboximidothioic acid.

14. The compound of claim 1 which is 7-(2-mercapto-2-phenylacetamido)cephalosporanic acid ester with in which R is alkyl of l to 6 carbon atoms; benthio g furancarboximidic acid in which A is a member selected from the group consisting of alkyl of l to 6 carbon atoms;

zamidomethyl; acetamidomethyl; 15. The compound of claim 1 which is 7-(2-mercapwcyanobenzyl; p y P' P y dimethyl' toacetamido) cephalosporanic acid ester with 3-iminoop y p y thiobutyrimidic acid.

16. The compound of claim 1 which is 7-(2-mercap- O toacetamido) cephalosporanic acid ester with Z-ben zamidothioacetimidic acid. I 17. The com ound of claim 1 which is 7-(2-merca 6]- i 5 i toacetamido) cephalosporanic acid ester with phenylthiobenzimidic acid.

18. The compound of claim 1 which is 7-(2-mercapto-Z-phenylacetamido)cephalosporanic acid ester with 3-iminothiobutyrimidic acid.

19. The compound of claim 1 which is 7-(2-mercaptoacetamido) cephalosporanic acid ester with N- ---NHCOCH- S --C phenylthioacetimidic acid.

H l 20. The compound of claim 1 which is 7-(2-mercap- BCH R NR toacetamido) cephalosporanic acid ester with Z-cyano- 2-phenylthioacetimidic acid. CO M 21. The compound of claim 1 which is 7-(2mercapand to-Z-phenylacetamido)cephalosporanic acid ester with 23. The compound of claim 1 which is 7-(2- 2-acetamidothioacetimidic acid. phenylacetamido) cephalosporanic acid diester with 22. The compound of claim 1 which is 7-(2-mercapdithiooxalimidic ester. toacetamido) cephalosporanic acid ester with phenyldithioimidocarbonic acid 7-phenyl ester. 

1. A COMPOUND OF THE FORMULA:
 2. A compound of claim 1 of the formula:
 3. The compound of claim 1 which is 7-(2-(p-dimethylamino-N-methylbenzimidoylthio)acetamido)cephalosporanic acid.
 4. The compound of claim 1 which is 7-(2-(p-chlorobenzimidoylthio)acetamido)cephalosporanic acid.
 5. The compound of claim 1 which is 7-(2-(acetimidoylthio) acetamido)cephalosporanic acid.
 6. The compound of claim 1 which is 7-(2-mercaptoacetamido) cephalosporanic acid ester with thioisonicotinimidic acid.
 7. The compound of claim 1 which is 7-(2-mercapto-2-phenylacetamido)cephalosporanic acid ester with thioisonicotinimidic acid.
 8. The compound of claim 1 which is 7-(2-mercaptoacetamido) cephalosporanic acid ester with N-(1-naphthyl)thiOacetimidic acid.
 9. The compound of claim 1 which is 7-(2-mercaptoacetamido) cephalosporanic acid ester with thio-2-thiophenecarboximidic acid.
 10. The compound of claim 1 which is 7-(2-mercaptoacetamido)-3-methyl-8-oxo-5-thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid ester with thio-2-thiophenecarboximidic acid.
 11. The compound of claim 1 which is 7-(2-mercaptoacetamido)-3-methyl-8-oxo-5-thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid ester with thionicotinimidic acid.
 12. The compound of claim 1 which is 7-(2-mercapto-2-phenylacetamido)cephalosporanic acid ester with N-(1-naphthyl)thioacetimidic acid.
 13. The compound of claim 1 which is 7-(2-mercaptoacetamido) acid ester acid with 5-oxo-3-phenyl-2-pyrazoline-1-carboximidothioic acid.
 14. The compound of claim 1 which is 7-(2-mercapto-2-phenylacetamido)cephalosporanic acid ester with thio-2-furancarboximidic acid.
 15. The compound of claim 1 which is 7-(2-mercaptoacetamido) cephalosporanic acid ester with 3-iminothiobutyrimidic acid.
 16. The compound of claim 1 which is 7-(2-mercaptoacetamido) cephalosporanic acid ester with 2-benzamidothioacetimidic acid.
 17. The compound of claim 1 which is 7-(2-mercaptoacetamido) cephalosporanic acid ester with N-phenylthiobenzimidic acid.
 18. The compound of claim 1 which is 7-(2-mercapto-2-phenylacetamido)cephalosporanic acid ester with 3-iminothiobutyrimidic acid.
 19. The compound of claim 1 which is 7-(2-mercaptoacetamido) cephalosporanic acid ester with N-phenylthioacetimidic acid.
 20. The compound of claim 1 which is 7-(2-mercaptoacetamido) cephalosporanic acid ester with 2-cyano-2-phenylthioacetimidic acid.
 21. The compound of claim 1 which is 7-(2-mercapto-2-phenylacetamido)cephalosporanic acid ester with 2-acetamidothioacetimidic acid.
 22. The compound of claim 1 which is 7-(2-mercaptoacetamido) cephalosporanic acid ester with phenyldithioimidocarbonic acid 7-phenyl ester.
 23. The compound of claim 1 which is 7-(2-phenylacetamido) cephalosporanic acid diester with dithiooxalimidic ester. 